Cyclic sulfone containing retroviral protease inhibitors

ABSTRACT

The present invention relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds and pharmaceutical or method of use therefor, particularly as an inhibitor of HIV protease.

CROSS REFERENCE

This application is a divisional of U.S. patent application Ser. No.08/556,883 filed Nov. 2, 1995 now U.S. Pat. No. 5,849,784, which is adivisional of U.S. patent application Ser. No. 07/998,187 filed Dec. 29,1992 now U.S. Pat. No. 5,514,801.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to cyclic sulfone moiety-containinghydroxyethylamine protease inhibitor compounds, a composition and methodfor inhibiting retroviral proteases such as human immunodeficiency virusinfection. The subject invention also relates to processes for makingsuch compounds as well as to intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitreplication of structural proteins and, more importantly, the retroviralprotease itself. In this manner, retroviral proteases can be effectivelyinhibited.

Several classes of mimetic compounds are known to be useful asinhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat.No. 4,599,198; G.B. 2,184,730; G.B. 2,209,752; EPO 264 795; G.B.2,200,115 and U.S. SIR H725; and U.S. Pat. No. 4,599,198 discloseurea-containing hydroxyethylamine renin inhibitors. However, it is knownthat, although renin and HIV proteases are both classified as aspartylproteases, compounds which are effective renin inhibitors generallycannot be predicted to be effective HIV protease inhibitors.

Several classes of mimetic compounds have been proposed, particularlyfor inhibition of proteases, such as for inhibition of HIV protease.Such mimetics include hydroxyethylamine isoteres and reduced amideisosteres. See, for example, EPO 346 847; EPO 342,541; Roberts et al,“Rational Design of Peptide-Bases Proteinase Inhibitors”, Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease”,Science, 249, 527 (1990). EPO 346 847 discloses certain N-heterocyclicmoiety-containing hydroxyethylamine protease inhibitor compounds, butdoes not suggest or disclose those of the present invention.

Dipeptide isosteres as inhibitors of HIV protease are found in EPapplication numbers 91309292, 91309028.8 and 91309302.7.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as cyclic sulfone- and either urea- orN-heterocyclic moiety-containing hydroxyethylamine inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided novelretroviral protease inhibiting compounds or a pharmaceuticallyacceptable salt, prodrug or ester thereof.

Generally, the present invention is a compound of the formula (I″)

and a pharmaceutically acceptable salt, prodrug or ester thereof;wherein Q, R² and R⁶ are as defined below and

W represents

wherein Y′ is as defined below; and

t represents 0,1 and 2, preferably 1;

t′ represents 1 and 2, preferably 1;

u represents 0, 1 and 2;

R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁸, R⁴⁹, R⁵⁰ and R⁵¹ independently representhydrogen and alkyl;

R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and independently represent hydrogen, alkyl andhydroxy; or

one of (a) R⁴⁰ together with R⁴⁸, (b) R⁴³ together with R⁴⁵, (c) R⁴⁵together with R⁴⁷, and (d) R⁴⁷ together with R⁴⁸ represent a bond; or

one of (a) R⁴⁴ together with R⁴⁵, (b) R⁴⁶ together with R⁴⁷ or (c) R⁵⁰together with R⁵¹ represent a double bond oxygen.

R⁴⁰ through R⁴⁸ most preferably represent hydrogen, however, both R⁴⁶and R⁴⁷ also preferably represent methyl at the same time R⁴⁰ throughR⁴⁵ and R⁴⁸ are all hydrogen. Additionally, R⁴⁸ is preferably hydrogenand the stereo configuration of the carbon to which R⁴⁸ is attached ispreferably in the configuration represented by the upper spot in Example4 set forth hereinafter, and preferably wherein the stereochemistryabout the hydroxy group may be designated as (R).

Thus, the present invention compound is preferably of the formula (I′)

or a pharmaceutically acceptable salt, prodrug or ester thereof; andwherein Q is:

and wherein t, Y′, R⁶, R², Y, R³, X, R⁴, R⁵, R^(4′) and R^(5′) are asdefined below, q represents 1 or 2;

R^(4″), R⁹ and R^(9′) independently represent radicals as defined by R³;

n represents 0 to 6;

R⁷ and R^(7′) independently represent radicals as defined for R³ andamino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine,glutamine, and t-butylglycine or R⁷ and R^(7′) together with the carbonatom to which they are attached form a cycloalkyl radical;

R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;

wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals.

A more preferred class of retroviral inhibitor compounds of the presentinvention are those represented by the formula (I)

or a pharmaceutically acceptable salt, prodrug or ester thereof, andwherein:

t represents either 0, 1 or 2;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkylradicals, which radicals are optionally substituted with a substituentselected from the group consisting of alkyl and halogen radicals, —NO₂,—CN, —CF₃, —OR₉, —SR⁹, wherein R⁹ represents hydrogen and alkylradicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, thioalkyl,alkylthioalkyl, and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

Y and Y′ independently represent O, S and NR¹⁵ wherein R¹⁵ representshydrogen and radicals as defined for R³;

X represents N, CH or O;

R⁴ and R⁵ independently represent hydrogen and radicals as defined byR³, or when X represents N, R⁴ and R⁵ together with the nitrogen atom towhich they are bonded represent heterocycloalkyl and heteroarylradicals, or when X represents CH, R⁴ and R⁵ together with the carbonatom to which they are bonded represent a cycloalkyl radical with theproviso R⁵ is nothing when X is O;

R⁶ represents hydrogen and alkyl radicals;

The compound of the formula I preferably includes a compound wherein Yand Y′ represent O, R⁶ represents hydrogen, t represents 1 and Xrepresents N.

Another compound of the formula I preferably includes a compound whereinR² represents benzyl, cyclohexylmethyl, n-butyl, 2-naphthylmethyl,p-fluorobenzyl and isobutyl.

Another compound of the formula I preferably includes a compound whereinR⁴ and R⁵ independently represent hydrogen, methyl, ethyl, isopropyl andtertiary-butyl.

Another compound of the formula I preferably includes a compound whereinR⁴ and R⁵ together with the nitrogen to which they are attachedrepresent a 5 to 8 membered heterocycloalkyl ring.

And finally, another compound of the formula I preferably includes acompound wherein R³ is isobutyl, n-butyl, isoamyl, benzyl,p-fluorobenzyl and cyclohexylmethyl.

Another more preferred class of retroviral inhibitor compounds of thepresent invention are those represented by the formula (II)

or a pharmaceutically acceptable salt, prodrug or ester thereof, andwherein:

t, R², Y′, and R⁶ represent radicals as defined above; and

R^(4′) and R^(5′) together with the nitrogen atom to which they arebonded represent an N-heterocyclic moiety.

A compound of the formula II preferably includes a compound wherein Y′represents O, t represents 1 and R⁶ represents hydrogen.

Another compound of the formula II preferably includes a compoundwherein R² represents benzyl, p-fluorobenzyl, cyclohexylmethyl,2-naphthylmethyl, n-butyl and isobutyl.

Another compound of the formula II preferably includes a compoundwherein NR^(4′)R^(5′) represents2-[[(1,1-dimethylethyl)amino]carbonyl]decahydroisoquinolinyl- or2-[[(1,1-dimethylethyl)amino]carbenyl]piperidinyl.

Another more preferred class of retroviral inhibitor compounds of thepresent invention are those represented by the formula (III)

or a pharmaceutically acceptable salt, prodrug or ester thereof, and

wherein t, Y′, R⁶, R² and R³ represent radicals as defined above; and

q represents 1 or 2; and

R^(4″) represents radicals as independently defined by R³.

A compound of the formula III preferably includes a compound wherein Y′represents O, t represents 1, R⁶ represents hydrogen and q represents 2.

Another compound of the formula III preferably includes a compoundwherein R² represents benzyl, p-fluorobenzyl, 2-naphthylmethyl,cyclohexylmethyl, n-butyl and isobutyl.

Another compound of the formula III preferably includes a compoundwherein R³ represents isobutyl, n-propyl, n-butyl, isoamyl,cyclohexylmethyl and cyclohexyl.

Another compound of the formula III preferably includes a compoundwherein R^(4″) represents an aryl or heteroaryl radical.

Another compound of the formula III preferably includes a compoundwherein R^(4″) represents a para-substituted phenyl wherein thesubstituent is hydrogen, fluoro, chloro, bromo, nitro, hydroxy, methoxyand amino.

Other more preferred classes are as follows:

or a pharmaceutically acceptable salt, prodrug or ester thereof;

wherein t, Y′, R⁶, R², R³, Y, q, R⁴, R⁵, R⁷, R^(7′), n and R⁸ are asdefined above.

A compound of the formula IV preferably includes a compound wherein Y′represents O, R⁶ represents hydrogen and q represents 2.

Another compound of the formula IV preferably includes a compoundwherein R² represents benzyl, p-fluorobenzyl, 2-naphthylmethyl, n-butyl,cyclohexylmethyl and isobutyl.

Another compound of the formula IV preferably includes a compoundwherein R³ represents isobutyl, n-propyl, n-butyl, isoamyl,cyclohexylmethyl and cyclohexyl.

Another compound of the formula IV preferably includes a compoundwherein R⁴ and R⁵ independently represent hydrogen, methyl, ethyl,isopropyl, t-butyl, phenyl and cyclohexyl or wherein R⁴ and R⁵ and thenitrogen to which they are attached represent a 5 to 8 memberedheterocycloalkyl ring.

A compound of the formula V preferably includes a compound wherein Y′represents O, R⁶ represents hydrogen, t represents 1, and q represents2.

Another compound of the formula V preferably includes a compound whereinR² represents benzyl, p-fluorobenzyl, 2-naphthylmethyl,cyclohexylmethyl, n-butyl, and iso-butyl.

Another compound of the formula V preferably includes a compound whereinR³ represents isobutyl, n-propyl, n-butyl, isoamyl, cyclohexylmethyl andcyclohexyl.

A compound of the formula VI preferably includes a compound wherein Yand Y′ both represent O, R⁶ represents hydrogen and t represents 1.

Another compound of the formula VI preferably includes a compoundwherein R² represents benzyl, p-fluorobenzyl, 2-naphthylmethyl,cyclohexylmethyl, n-butyl, and isobutyl.

Another compound of the formula VI preferably includes a compoundwherein R³ represents isobutyl, n-propyl, isoamyl, n-butyl,cyclohexylmethyl, benzyl, p-fleorobenzyl and p-methoxybenzyl.

Another compound of the formula VI preferably includes a compoundwherein R⁷ and R^(7′) independentyly represent hydrogen, methyl andethyl, or together with the carbon to which they are attached representa 3 to 6 membered cycloalkyl ring.

The most preferred compounds of the present invention are those of theformula I through VI wherein t is 1, R⁶ is hydrogen, and R² is anaralkyl, alkyl or cycloalkylalkyl radical.

Each of the compounds of the present invention is represented by formulahaving at least three optically active carbon centers. The presentinvention is meant to include compounds having each of the combinationsof optical rotation and mixtures thereof. The present compounds may haveadditional stereoisomers and thus is also meant to include each of suchisomers.

In each of the Formula I, II, III, IV, V, and VI a preferred structureis one where stereo configuration of the group —C(OH)—shown by the OH onthe carbon adjacent the carbon having R² attached is represented by thestereochemistry designated as (R).

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to about 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. The term“thioalkyl” means aralkyl radical having at least one sulfur atom,wherein alkyl has the significance given above. An example of athioalkylis —C(CH₃)₂SCH₃. The corresponding sulfoxide and sulfone of thisthioalkyl are —C(CH₃)₂S(O)CH₃ and —C(CH₃)₂S(O)₂CH₂, respectively. Theterm “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to about 8carbon atoms. Examples of suitable alkenyl radicals include ethenyl,propenyl, alyl, 1,4-butadienyl and the like. The term “alkynyl”, aloneor in combination, mans a straight-chain hydrocarbon radical having oneor more triple bonds and containing from 2 to about 10 carbon atoms.Examples of alkynl radicals include ethynyl, propynyl (propargyl),butynyl and the like. The term “alkoxy”, alone or in combination, meansan alkyl ether radical wherein the term alkyl is as defined above.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like. The term “cycloalkyl”, alone or in combination, means an alkylradical which contains from about 3 to about 8 carbon atoms and iscyclic. Examples of such cycloalkyl radicals include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. The term“cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from about 3 to about 6, carbon atoms. The term “aryl”, aloneor in combination, means a phenyl or naphthyl radical which optionallycarries one or more substituents selected from alkyl, alkoxy, halogen,hydroxy, amino, nitro and the like, such as phenyl, p-tolyl,4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like. The term“aralkyl”, alone or in combination, means an alkyl radical as definedabove in which one hydrogen atom is benzyl, 2-phenylethyl and the like.The term “aralkoxy carbonyl”, alone or in combination, means a radicalof the formula —C(O)—O—aralkyl in which the term “aralkyl” has thesignificance given above. An example of an aralkoxycarbonyl radical isbenzyloxycarbonyl. The term “aryloxy”, alone or in combination, means aradical of the formula aryl-O— in which the term “aryl” has thesignificance given above. The term “alkanoyl”, alone or in combination,means an acyl radical derived from an alkanecarboxylic acid, examples ofwhich include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, andthe like. The term “cycloalkylcarbonyl” means an acyl group derived froma monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,4-phenylbutyryl, (1-naphthyl)acetyl, derived from a monocylic or bridgedcycloalkanecarboxylic acid such as cyclopropanecarbonyl,cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cycloalkanecarboxylic acid which is optionallysubstituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-phenylbutyryl, (1-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term “aroyl” means an acyl radical derived from anaromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like. The heterocyclyl orheterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, orheterocyclylalkyl group or the like is a saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic heteroycle which containsone or more hetero atoms selected from nitrogen, oxygen and sulphur,which is optionally substituted on one or more carbon atoms by halogenalkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom(i.e., —NH—) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkylor on a tertiary nitrogen atom (i.e., +N−) by oxido and which isattached via a carbon atom. The heteroaryl portion of a heteroaroyl,heteroaryloxycarbonyl, or heteroaralkoxycarbonyl group or the like is anaromatic monocyclic, bicyclic, or tricyclic heterocycle which containsthe hetero atoms and is optionally substituted as defined above withrespect to the definition of heterocyclyl. Examples of such heterocyclyland heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl(e.g., 2-indolyl, etc.), quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetra hydroquinolinyl (e.g.,1,2,3,4-tetrahydro-1-oxoisoquinolinyl, etc), quinoxalinyl,beta-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4-, or 5-benzimidazolyl,and the like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-O-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocyclylalkanoyl” is an acyl radical derivedfrom a heterocyclyl-substituted alkane carboxylic acid whereinheterocyclyl has the significance given above. The term“heterocyclyloxycarbonyl” means an acyl group derived fromheterocyclyl-O—COOH wherein heterocyclyl is as defined above. The term“heterocyclylalkanoyl” means an acyl radical of the formulaaryl-O—alkanoyl wherein aryl and alkanoyl have the significance givenabove. The term “heterocyclylalkoxycarbonyl” means an acyl radicalderived from heterocyclyl-substituted alkane-O—COOH wherein heterocyclylhas the significance given above. The term “heteroaryloxycarbonyl” meansan acylradical derived from a carboxylic acid represented byheteroaryl-O—COOH wherein heteroaryl has the significance given above.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl(carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group continuing substituentsselected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like. The term “aminoalkanoyl” means anacyl radical derived from an amino substituted alkanecarboxylic acidwherein the amino group can be a primary, secondary or tertiary aminogroup containing substituents selected from the group consisting ofhydrogen, cycloalkyl, cycloalkylalkyl radicals and the like, examples ofwhich include N, N-dimethylaminoacetyl and N-benzylaminoacetyl. The term“halogen” means fluorine, chlorine, bromine or iodine. The term “leavinggroup” generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known and include carboxylates, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates, —OR and —SR andthe like. Preferred leaving groups are indicated herein whereappropriate. The term “N-heterocyclic moiety” is a heterocyclic radicalwith a nitrogen radical bond site which may be a heterocycloalkyl orheteroaryl, wherein heterocycloalkyl and heteroaryl have thesignificance given above, with the addition that polycyclic heteroarylmay be fully aromatic or partially aromatic, for example, a fusedheterocycloalkylaryl and a fused heteroarylcycloalkyl, andheterocycloalkyl and cycloalkyl may also be bridged. Preferably, theN-heterocyclic moiety has 5, 6 or 7 members when monocyclic; 5, 6 or 7members in a ring with 1, 2 or 3 members in a bridge when a bridgedmonocyclic; 11, 12 or 13 members when bicyclic; and 11 to 16 memberswhen tricyclic.

Examples of N-heterocyclic moieties include, but are not limited to,those represented by the following formulas:

wherein:

R²⁰ represents hydrogen, alkyl, alkoxycarbonyl, monoalkylcarbamoyl,monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula:wherein:

R¹⁰ and R¹¹ each represents alkyl;

R¹² represents hydrogen, hydroxy, alkoxycarbonylamino or acylamino;

R¹³ represents hydrogen, alkyl, aryl, alkoxycarbonyl or acyl;

m is 1, 2, 3, or 4;

p is 1 or 2; and

r is independently 0, 1 or 2.

Procedures for preparing the compounds of Formulas I, II, III, IV, V andVI are set forth below. It should be noted that the general procedure isshown as it relates to preparation of compounds having the specifiedstereochemistry, for example, wherein the stereochemistry about thehydroxy group is designated as (R). However, such procedures aregenerally applicable to those compounds of opposite configuration, e.g.,where the stereochemistry about the hydroxyl group is (S). The terms (R)and (S) configuration are as defined by the IUPAC 1974 Recommendationsfor Section E, Fundamental Stereochemistry, Pure appl. Chem. (1976) 45,13-30.

Likewise, procedures to obtain the preferred stereochemistry and itsopposite configuration for the carbon to which R⁴⁸ is attached, andparticularly when R⁴⁸ is hydrogen, are generally applicable from thatdisclosed in Example 4 below.

Preparation of Compounds of Formula I, III, IV, V and VI

Preparation of the compounds of Formula I are accomplished by preparinga cyclic sulfone carboxylic acid according to the following Scheme 1 andScheme 1a:

Exemplary conditions for the preparation of Scheme 1 are found inPreparation 1 hereinafter. For a cyclic sulfone having a seven memberedring the corresponding starting material may be substituted usinganalogous reaction conditions. On the other hand, for a cyclic sulfonehaving a five membered ring, the known starting material,3-methoxy-carbonyl-2,5-dihydrothiophene-1,1-dioxide is hydrogenated anddeesterified in a manner analogous to the last two steps shown in Scheme1 and exemplified in Preparation 2 hereinafter.

A urea isostere of the formula A, the formula B, or the formula C thatis prepared according to the methods of PCT Number WO-PCT/US92/8613 orPCT Application Number PCT/US92/08700, and PCT/US91/8593, respectively,which are incorporated by reference therefor, is then coupled with thecyclic sulfone carboxylic acid prepared above to obtain the compound ofthe formula I or VI in the manner set out in Scheme 2 hereinafter:

Suitable coupling agents are well-known in the art and includedicyclohexylcarbodiimide or diisopropylcarbodiimide. The coupling isconducted at a temperature of from 20° C. to about 50° C., preferably atabout 25° C., in a suitable solvent system such as, for example,N,N-dimethylformamide, and the like. The amino protecting groups arethose known in the art and include carbobenzoxy, butyryl,t-butoxycarbonyl, acetyl, benzoyl and the like, preferable carbobenzoxyand t-butoxycarbonyl.

Preparation of the Compounds of Formula II

The cyclic sulfone carboxylic acid is again prepared as set out above inScheme 1.

An amino epoxide, which is a mixture of diastereomers of thecorresponding amino-protected epoxides of the formulas:

is prepared by the processes shown in patent application Ser. No.PCT/US91/8617 and is incorporated by reference therefor. P¹ and P²independently represent hydrogen and amino-protection groups well knownin the art and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl,benzoyl and the like, preferably carbobenzoxy and t-butoxycarbonyl,acetyl, benzoyl and the like, preferably carbobenzoxy andt-butoxycarbonyl; and R² represents a radical as set out above. Thesediastereomers can be separated by chromatography or, alternatively, oncereacted in subsequent steps the diastereomeric products can beseparated.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, of the formula:

HNR^(4′)R^(5′)

wherein R^(4′) and R^(5′) are as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 60 C. toabout 120 C. in an inert organic solvent, but is preferably, but notnecessarily, conducted at a temperature at which the solvent begins toreflux. Suitable solvent systems include those wherein the solvent is analcohol, such as methanol, ethanol, isopropanol, and the like, etherssuch as tetrahydrofuran, dionane and the like, toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Examples of amines corresponding tothe formula HNR^(4′)R^(5′) include those having the following formula:

wherein R²⁰, R¹⁰, R¹¹, R¹², R¹³, m, p and r have the significance givenabove, and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-NR⁴R⁵-propan-2-ol derivative (hereinafter referred to asan amino alcohol) is an intermediate which contains the desiredN-heterocyclic moiety or intermediate thereof and can be represented bythe formula:

wherein P¹, P², R², R^(4′) and R^(5′) are as described above.

Alternatively, the compounds of the present invention represented byFormula II above can be prepared utilizing the following generalprocedure. An N-protected haloketone derivative of an amino acid; alsoprepared by methods in patent application Ser. No. PCT/US91/8617 andincorporated by reference therefor, having the formula:

wherein P¹ and P² represent amino protecting groups, R² is as definedabove, and Z represents a chlorine, bromine or iodine atom, is reacted,in a suitable inert organic solvent system, with an equal amount of adesired amine of the formula:

HNR^(4′)R^(5′)

 wherein R^(4′) and R^(5′) are as defined above. The reaction yields acompound of the general formula(5):

wherein P¹, P², R², R^(4′) and R^(5′) have the significance givenearlier.

The reaction of the N-protected haloketone derivative of an amino acid,preferably one in which P¹ and P² represent benzyloxy carbonyl, with thedesired amine, a heterocyclic compound of formula HNR⁴R⁵, can be carriedout in any known manner, for example, in an inert organic solvent suchas halogenated aliphatic hydrocarbon (e.g., dichloromethane,N,N-dimethylformamide, tetrahydrofuran, isopropanol and ethanol) and inthe presence of a base (e.g., a trialkylamine such as triethylamine anddiisopropylethyl amine, sodium bicarbonate, DBU and the like,conveniently at about room temperature.

The reduction of the aminoketone compound of Formula 5 results in acompound of the general formula (6):

wherein P¹, P², R², R⁴ and R′^(5′) have the significance given earlier.The reduction of the aminoketone compound of Formula 5 to theN-heterocyclic moiety-containing derivative (Formula VI) can be carriedout according to known methods for the reduction of a carbonyl group toa hydroxy group. Thus, for example, the reduction can be carried outusing a complex metal hydride such as an alkali metal borohydride,especially sodium borohydride, in an appropriate organic solvent such asalkanol (e.g., methanol, ethanol, propanol, isopropanol, etc.).Conveniently, the reduction is carried out at about room temperature.

Then this N-heterocyclic moiety-containing derivative having an aminoprotecting group P is or P¹ and P² are, removed under conditions whichwill not affect the remaining portion of the molecule. These methods arewell known in the art and include acid hydrolysis, hydrogenolysis andthe like. A preferred method involves removal of the protecting group,e.g., removal of a carbobenzoxy group, by hydrogenolysis utilizingpalladium on carbon in a suitable solvent system such as an alcohol,acetic acid, and the like or mixtures thereof. Where the protectinggroup is N,N-dibenzyl, these groups may be removed by hydrogenolysisutilizing palladium on carbon. Where the protecting group is at-butoxycarbonyl group, it can be removed utilizing an inorganic ororganic acid, e.g., HCl or trifluoroacetic acid, in a suitable solventsystem, e.g., dioxane or methylene chloride. The resulting product isthe amine salt derivative.

Following neutralization of the salt, the amine is then reacted with acyclic sulfone carboxylic acid as prepared above to produce theantiviral compounds of the present invention having the formula II alsoas defined above. The reaction of the amine with a cyclic sulfonecarboxylic acid is as shown in the following Scheme 3:

Conditions of the Scheme 3 are generally as follows. The cyclic sulfonecarboxylic acid can be coupled to any of the desired isosteres usingmethods well known to those in the art. For example, activation of theacid can be accomplished using dicyclocarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in thepresence of N-hydroxybenzotriazole in a suitable solvent, such asN,N-dimethylformamide, tetrahydrofuran or methylene chloride.Alternately, the acid can be activated by treatment withN,N-disuccinimidyl carbonate and pyridine. The resulting active esterscan then be reacted with the desired isostere, optionally with a base(such as diisopropylethylamine) present, to afford the desired cyclicsulfone containing retroviral protease inhibitors.

The R⁶ substituent is then added according to the analogous proceduresalso described in PCT/US91/8613 and WO09208700, incorporated byreference therefor.

Finally, an amino alcohol is prepared by reacting the amino epoxidedescribed above or a corresponding haloalcohol with R³NH₂ also in amanner described in U.S. patent application Ser. No. PCT/US91/8617incorporated by reference therefor to obtain the compound of theformula:

wherein P, R² and R³ are as defined above.

The amino alcohol defined above is then reacted in a suitable solventwith a sulfonyl chloride (R⁴SO₂Cl) or sulfonyl anhydride in the presenceof an acid scavenger. Suitable solvents in which the reaction can beconducted include methylene chloride, tetrahydrofuran and the like.Suitable acid scavengers include triethylamine, pyridine and the like.Preferred sulfonyl chlorides are methanesulfonyl chloride andbenzenesulfonyl chloride. The resulting sulfonamide derivative can berepresented, depending on the epoxide utilized by the formulas:

wherein P, P¹, P², R², R³ and R^(4″) are as defined above.

The sulfonyl halides of the formula R^(4″)SO₂X can be prepared by thereaction of a suitable Grignard or alkyl lithium reagent with sulfurylchloride, or sulfur dioxide followed by oxidation with a halogen,preferably chlorine. Also, thiols may be oxidized to sulfonyl chloridesusing chlorine in the presence of water under carefully controlledconditions. Additionally, sulfonic acids may be converted to sulfonylhalides using reagents such as PCl₅, and also to anhydrides usingsuitable dehydrating reagents. The sulfonic acids may in turn beprepared using procedures well known in the art. Such sulfonic acids arealso commercially available. In place of the sulfonyl halides, sulfinylhalides (R⁴SOX) or sulfenyl halides (R⁴SX) can be utilized to preparecompounds wherein the —SO₂— moiety is replaced by an —SO— or —S— moiety,respectively.

A cyclic sulfone of the formula I′ wherein Q is represented by (4) or(5) above is prepared in a like manner.

For example, an intermediate, the amino alcohol, is reacted as shown inthe following Scheme 3A.

In other words, the amino alcohol defined above is then reacted in asuitable solvent with a sulfamoyl halide, e.g., sulfamoyl chloride(R⁴R⁵NSO₂Cl or R⁴HNSO₂Cl) or corresponding sulfamoyl anhydride in thepresence of an acid scavenger. Suitable solvents in which the reactioncan be conducted include methylene chloride, tetrahydrofuran. Suitableacid scavengers include triethylamine, pyridine. The resulting sulfamicacid derivative can be represented, depending on the epoxide utilized,by the formulas:

wherein P, P¹, P², R², R³, R⁴ and R⁵ are as defined above. Theseintermediates are useful for preparing inhibitor compounds of thepresent invention and are also active inhibitors of retroviralproteases.

The sulfamoyl halides of the formula R⁴NHSO₂X can be prepared by thereaction of a suitable isocyanate of the formula R⁴NCO with fumingsulfuric acid to produce the corresponding sulfamate which is thenconverted to the halide by well known procedures, such as by treatingthe sulfamate with PCl₅. Alternatively, the isocyanate can be treatedwith chlorosulfonic acid to produce the corresponding sulfamoyl chloridedirectly.

The sulfamoyl halides of the formula R⁴R⁵NSO₂Cl can be prepared byreacting an amine of the formula R⁴R⁵NH, preferably as a salt such asthe hydrochloride, with sulfuryl chloride in a suitable solvent such asacetonitrile. The reaction mixture is gradually warmed to refluxtemperature and maintained at the reflux temperature until the reactionis complete. Alternatively, sulfamoyl halides of the formula R⁴R⁵NSO₂Clcan be prepared by reacting an amine of the formula R⁴R⁵NH with sulfurylchloride in boiling MeCN as disclosed in Matier et al., J. Med. Chem.,15, No.5, p. 538 (1972).

In an analogous manner a sulfamoyl halide, preferably Cl, of theformula:

is reacted with the amino alcohol as defined above.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or p¹ and p² is removed under conditions which willnot affect the remaining portion of the molecule. These methods are wellknown in the art and include acid hydrolysis, hydrogenolysis and thelike. A preferred method involves removal of the protecting group, e.g.,removal of a carbobenzoxy group, by hydrogenolysis utilizing palladiumon carbon in a suitable solvent system such as an alcohol, acetic acid,and the like or mixtures thereof. Where the protecting group is at-butoxycarbonyl group, it can be removed utilizing an inorganic ororganic acid, e.g., HCl or trifluoroacetic acid, in a suitable solventsystem, e.g., dioxane or methylene chloride. The resulting product isthe amine salt derivative. Where the protecting group is a benzylradical, it an b removed by hydrogenolysis. Following neutralization ofthe salt, the amine, D, E or F, is then reacted with a cyclic sulfone asdescribed below and shown as follows:

wherein R², R³, R^(4″) and q is as defined above.

The conditions of the reaction in Scheme 4 include suitable solventsystems, such as, generally, recited following Scheme 3 above.

In order to prepare the tetrahydrothiopyran-4-carboxamide sulfone andits analogs, one can start from the commercially availabletetrahydrothiopyran-4-one (compound 1 in Scheme 5). The ketone 1 can bereduced to the alcohol 2 using a variety of methods including sodiumborohydride or lithium aluminum hydride. The alcohol can then beconverted into a leaving group X, such as chloro, bromo, iodo,O-methanesulfonate, or O-p-toluenesulfonate, of the like. The leavinggroup X is then displaced with a cyanide source, such as sodium cyanide,potassium cyanide, lithium cyanide or tetra-n-butylammonium cyanide, ina suitable solvent, such as dimethyl sulfoxide, N,N-dimethylformamide orN-methylpyrrolidinone, to provide the cyanide 4. The cyano group canthen be hydrolyzed under a variety of conditions well known to thoseskilled in the art. The hydrolysis to the acid 6 can either beaccomplished directly in one step or using a two step procedureinvolving the amide 5. Thus the cyano compound 4 can be converted to theamide 5 using concentrated sulfuric acid, and the amide converted to theacid using sodium hydroxide or potassium hydroxide in aqueous methanolor ethanol. Alternatively, the cyano compound 4 can be directlyhydrolyzed to the acid 6using concentrated hydrochloric acid at reflux.The sulfur in acid 6 can then be oxidized to the sulfone by variousmethods, such as, meta-chloroperbenzoic acid, sodium perborate in aceticacid, or hydrogen peroxide in acetic acid, using greater than twoequivalents of oxidizing agent. If one desires the sulfoxide, ratherthan the sulfone, one can use one equivalent of oxidizing agent. Theacids 6 and 7 can readily be converted to the compounds of thisinvention by reaction with various isosteres using standard couplingtechniques. It is envisioned that through appropriate modifications ofthe sequence of reactions in Scheme 5, a variety of analogs can be madewith substituents on the tetrahydrothiopyran ring.

Further, a compound of the present invention wherein W is a heterocyclicring having a substituent other than hydrogen represented as R⁴⁰, R⁴¹,R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ or R⁴⁸ can be prepared by the method andScheme showing the method in the following manner.

In order to prepare the thiomorpholine analog of the cyclic sulfone, asshown in Scheme 6, one can start with either D-, L-, or D,L-cysteine.Reaction of cysteine or an ester of cysteine (compound 8, Scheme 6),where R₁ is hydrogen, methyl, ethyl, t-butyl, benzyl or other carboxylprotecting groups with a species X—CKH₂CO₂R₂, where X is a leaving groupas defined above and R² is independently hydrogen, methyl, ethyl,t-butyl, benzyl or other carboxyl protecting groups, in the presence ofa base such as sodium bicarbonate, triethylamine, or the like providesthe cyclic sulfide 9. The sulfide 9 can then be oxidized to either thesulfoxide or sulfone using the methods described above. If necessary,the carboxyl protecting group can be removed from 9 or 10 and theresulting carboxylic acid coupled to the various isosteres usingstandard methods. It is also envisioned that one could use D-, L- orD<L-penicillamine [HSC(CH₃)₂CH(NH²)CO²H] in place of cysteine 8. It isalso contemplated that appropriate modifications of the sequence wouldprovide a variety of analogs.

For compounds wherein the oxidation state of the cyclic sulfur in the Wsubstituent is within that of the desired product, the oxidation ofSchemes 1 and 1a can be performed with a suitable oxidizing agent; suchas hydrogen peroxide, sodium perborate or meta-chloroperbenzoic acid. Itis well known to those skilled in the art that this oxidation can becotrolled through the use of one equivalent of oxidizing agent toprovide the sulfoxide or at least two or more equivalents to provide thethe sulfone.

Where a substituent is designated as, or can be, a hydrogen, the exactchemical nature of a substituent which is other than hydrogen at thatposition, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino andthe like functional group, is not critical so long as it does notadversely affect the overall activity and/or synthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable form known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the following examples, melting points were determined on aFisher-Johns melting point apparatus and are uncorrected. All reagentswere used as received without purification. All proton and carbon NMRspectra were obtained on either a Varian VXR-300 or VXR-400 nuclearmagnetic resonance spectrometer using tetramethylsilane as internalstandard. Gas chromatograph was performed on a Varian 3400chromatography system. All instruments were utilized according to themanufacturer's directions.

EXAMPLES Example 1

Preparation of the cyclic sulfone carboxylic acid of the formula:

Part A: Preparation of methyltetrahydro-2H-thiopyran-4-keto-3-carboxylate

To a suspension of 55.1 gm (1.02 mole) of dry, powdered sodium methoxidein anhydrous ether (200 mL) at 0° C. was added 56.8 mL (0.33 mole)dimethyl 3,3-thiodipropionate dropwise. The reaction mixture was stirredunder nitrogen, warming to room temperature over 1 hour, and thenrefluxed for 4.5 hrs. Subsequently, the suspension was stirred at roomtemperature for 17 hrs. upon which was added a solution of acetic acid(100 mL) in H₂O (300 mL) slowly at 0° C. The aqueous layer was extractedthree times with diethylether. The combined ether layers were washedthree times with saturated sodium bicarbonate and one time withsaturated sodium chloride. The organic layer was dried with MgSO₄ andconcentrated in vacuo to give a pale yellow oil which was partiallypurified by vacuum distillation to give 21.11 gm (114-124° fraction/1.5mm) of oil which was further purified by flash chromatography on 1 kgsilica gel with 4-5% ethyl acetate in hexane to give 19.48 gm (34%) pureoil which crystallized upon standing; mass spectrum m/e=174 (EI,M+).

Part B: Preparation of methyltetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate

To a −78° C. solution of 5.91 gm (0.0339 moles) of methyltetrahydro-2H-thiopyran-4-keto-3-carboxylate in anhydrous methylenechloride (100 mL) and anhydrous methanol (100 mL) was added 0.644 gm(0.017 mole) soldium borohydride under N₂ over a period of 6 hrs. Thereactor was alloed to warm to 0° C. over 1 hr upon which was added H₂O(100 mL), slowly at first. The organnic solvents were removed in vacuo.The aqueous residue was extracted 4 times with methylene chloride. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated in vacuo to give 4.93 gm (83% crude yield) of a 2:1mixture of cis;trans methyltetrahydro-2H-thriopyran-4-hydroxy-3-carboxylate as an oil; massspectrum m/e=176 (EI,M+).

Part C: Preparation of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate

To a solution of 4.93 gm (0.0279 mole) of methyltetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B in anhydrousmethylene chloride (25 mL) was added 6.77 mL (0.0837 mole) anhydrouspyridine. The solution was cooled to 0° C., upon which was added 3.25 mL(0.0420 mole) methanesulfonyl chloride, dropwise via syringe. Thesolution was allowed to warm to room temperature and stirred under N₂for 7.5 hrs. The reaction was then cooled to 0° C. and an additional0.648 mL (0.00837 mole) of methanesulfonyl chloride was added. Thesolution was stirred at room temperature an additional 16 hrs. uponwhich ethyl acetate (125 mL) was added. The organic layer was washedwith dilute HCl, saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered, and concentrated invacuo to give a mixture of the cis and trans mesylate and unreactedmethanesulfonyl chloride. The crude mesylate mixture was dissolved inanhydrous methylene chloride (30 mL) upon which was added 12.68 mL(0.0911 mole) triethyl amine. The reaction was stirred under N₂ for 7hrs. upon which was added 8.5 mL (0.061 mole) triethyl amine and thesolution stirred 17 more hrs. The organic layer was washed once withdilute acid and once with saturated sodium chloride, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography on 300 gm silica gel with4-25% ethyl acetate in hexane to give 2.76 gm (63%) of methyl5,6-dihydro-2H-thiopyran-3-carboxylate as a clear oil; mass spectrumm/z=159 (CI,M+H)

Part D: Preparation of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate,1,1 dioxide

To a solution of 0.934 gm (5.75 mmol) of5,6-dihydro-2H-thiopyran-3-carboxylate from part C in glacial aceticacid (40 mL) was added 1.98 gm (12.88 mmole) sodium perborate. Thereaction mixture was stirred at 55° C. under N₂ for 19 hrs. whereuponthe solution was poured into H₂O (50 mL) and neutralized with 50% NaOHto pH=7. The solution was extracted three times with methylene chloride.The combined organic layers were washed once with saturated sodiumbicarbonate and once with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated in vacuo to give 0.832 gm(76%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide as awhite solid; mass spectrum m/e=190 (EI, M+)

Part E: Preparation of methyl-2H-thiopyran-3-carboxylate, 1,1-dioxide

A solution of 832 mg (4.37 mmole) of5,6-dihydro-2H-thiopyran-3-carboxylate,1,1 dioxide from part D inmethanol (40 mL) was hydrogenated in the presence of 400 mg (50% wt) of10% Pd/charcoal for 4 hrs. at room temperature and 50 psig of H₂. Thecatalyst was removed by vacuum filtration through a short plug of packedcelite and the solvent removed in vacuo to give 802 mg (96%) of methyl2H-thiopyran-3-carboxylate, 1,1-dioxide as a white solid; mass spectrumm/z=193 (CI,M+H)

Part F: Preparation of 2H-thiopyran-3-carboxylate, 1,1-dioxide

To a solution of 789 mg(4.10 mmole) of methyl2H-thiopyran-3-carboxylate, 1,1-dioxide from part E in 4N HCl/dioxane(10 mL) was added H₂O (5 mL) slowly. The reaction was stirred at roomtemperature for 116 hrs. whereupon the solvent was removed in vacuo. Thecrude material was recrystallized from a mixture of ethyl acetate andhexane to give 613 mg (84%) of 2H-thiopyran-3-carboxylate,1,1 -dioxideas a white solid; mass spectrum m/z=179 (CI, EI,M+H)

Alternatively, one can separate the isomers from part B.

Part B2: Preparation of cis methyltetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate

To a −78° C. solution of 6.01 gm (0.0345 mol) of methyltetrahydro-2H-thiopyran-4-keto-3-carboxylate from part A in anhydrousmethylene chloride (100 mL) and anhydrous methanol (100 mL) was added0.65 gm (0.0172 mol) sodium borohydride under N₂ over a period of 3 hrs.The reaction was allowed to warm to 0° C. over 1 hour upon which wasadded H₂O (100 mL), slowly at first. The organic solvents were removedin vacuo. The aqueous residue was extracted 4 times with methylenechloride. The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified by flash chromatography on 300 gm silica gel and diluted with 1to 1.5% methanol in methylene chloride to give 1.80 gm (30%) of the cisisomer as a clear oil; mass spectrum m/z=177 (FAB,M+H).

Part C2: Preparation of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate

To a solution of 1.79 gm (0.0101 mol) of cis-methyltetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B2 inanhydrous methylene chloride (10 mL) was added 2.45 mL (0.0303 mol)anhydrous pyridine. The solution was cooled to 0° C., upon which wasadded 1.18 mL (0.0152 mol) methanesulfonyl chloride, dropwise viasyringe. The solution was allowed to warm to room temperature andstirred under N₂ for 4 hrs., whereupon the reaction was cooled to 0° C.and an additional 1.6 mL (0.020 mol) anhydrous pyridine and 1.18 mL(0.0152 mol) methanesulfonyl chloride were added. The solution wasstirred at room temperature for 48 hrs. upon which ethyl acetate (50 mL)was added. The organic layer was washed with dilute HCl, saturatedsodium bicarbonate, and saturated sodium chloride, dried over magnesiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography on 200 gm silica with 20-33% ethylacetate in hexane to give 2.18 gm (85%) of the cis mesylate whichcrystallized upon standing. The pure mesylate (2.15 gm; 8.45 mmol) wasdissolved in anhydrous methylene chloride (8 mL) upon which was added3.53 mL (25.3 mmol) of triethyl amine and the solution stirred for 17hrs. An additional 2.35 mL (16.9 mmol) of triethyl amine was added andthe reaction stirred for 2 more hrs. The organic layer was washed withdilute HCl and saturated sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo to give 1.29 gm (96%) of methyl5,6-2H-thiopyran-3-carboxylate as a clear oil; mass spectrum m/z=159(CI,M+H), which was identical to the material from part C of example 1.

Example 2 Preparation of tetrahydrothiophene-3-carboxylic acid,1,1-dioxide

Part A: Preparation of methyl tetrahydrothiophene-3-carboxylic acid,1,1-dioxide

To 3-methoxycarbonyl-2,5-dihydrothiophene-1,1-dioxide (5.0 g, 2.9×10⁻²mol) in deoxygenated MeOH (60 ml) was added 10% Pd on carbon (0.5 g) andthe resulting suspension hydrogenated at 50 psi for 48 hours.Subsequently, the catalyst was removed by filtration through celite, andthe filtrate concentrated in vacuo to give a pale oil (4.23 g, 84%);mass spectrum, m/z 179 (CI, M+H).

Part B: Preparation of tetrahydrothiophene-3-carboxylic acid,1,1-dioxide

To the ester from part A (4.23 g, 2.4×10⁻² mol) in MeOH (75 ml) at 0° C.was added lithium hydroxide (1.01 g, 2.4×10⁻² mol) in water (80 ml) andthe resulting solution stirred, warming to ambient temperature over 6.5hours. The MeOH was removed in vacuo and the residue neutralized with2.5N NaOH and extracted repeatedly with CH₂Cl₂. The combined organicextracts were dried over MgSO₄, filtered, and concentrated in vacuo togive an oil which was triturated in CH₃OH (25 ml). The solids wereremoved by filtration and the filtrate concentrated in vacuo to give apale oil (0.57 g, 15%); mass spectrum, m/z 165 (CI, M+H).

Example 3[1S-[1R*(R*),2S*]]-N¹[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-1-hydroxy-1-(phenyl-methyl)propyl]-2-amino]butanediamide

Protected[1S-[1R*(R*),25*]]-N¹[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-1-hydroxy-1-(phenyl-methyl)propyl]-2-amino]butanediamideis prepared by methods disclosed or methods analogous thereinPCT/US91/8613 which is incorporated by reference therefor.

Example 4 Preparation of 2H-thiopyran-3-carboxamide,N-[3-[[[(1,1-dimethylethylamino]-carbonyl](3-methylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]tetrahydro,-1,1-dioxide3S-[3R*(1R*,2S*)]]-

and

[3R-[3R*(1R*,2S*)]]-

Part A

The following amine is prepared by deprotecting the compound prepared inExample 3 above by procedures disclosed in PCT/US91/8613.

Part B

To a 0° C. solution of 93.5 mg (0.525 mmole) of2H-thiopyran-3-carboxylate, 1,1-dioxide in anhydrous dimethyl formamide(1 mL) was added 115 mg (0.75 mmole) of hydroxybenzotriazole and 105 mg(0.55 mmole) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC). The solution was stirred under N₂ for 2 hrs. at 0°C. upon which was added 175 mg (0.50 mmole) of amine from part A andstirring continued for 48 hrs. at room temperature. The solvent wasremoved in vacuo and redissolved in ethyl acetate whereupon it waswashed with 5% citric acid, saturated sodium bicarbonate, and saturatedsodium chloride. The organic layer was dried with magnesium sulfate,filtered and concentrated in vacuo to give 214 mg (84% of crudematerial.

The 2 diastereomers were purified by flash chromatography on 21 grams ofsilica gel and eluted with 50-85% ethyl acetate in hexane to give 30 mgof each diasteromer as a white solid; mass spectrum

upper spot m/z=516 (FAB,M+Li)

lower spot m/z=516 (FAB,M+Li)

Example 4a

In an analogous manner using appropriate corresponding startingmaterials a compound of the following formula is prepared.

Example 5 Preparation of thiophene-3-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]-carbonyl](3-methylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]tetrahydro,-1,1-dioxide,[3S-[3R*(1R*,2S*]]-

and

Preparation of thiophene-3-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]-carbonyl](3-methylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]tetrahydro,-1,1-dioxide,[3R-[3R*(1R*,2S*)]]-

(and its isomer)

To the acid from Preparation 2 (0.25 g, 1.5×10⁻³ mol) in anhydrous DMF(3 ml) was added hydroxy-benzotriazole (0.40 g, 3.0×10⁻³ mol) and1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (0.41 g,2.1×10⁻³ mol) and the resulting solution stirred for 5 minutes.Subsequently was added the amine from Example 4 Part A (0.44 g, 1.3×10⁻³mol) in anhydrous DMF (4 ml) and the reaction mixture stirred under anitrogen atmosphere for 23 hours, upon which it was poured into 60%saturated NaHCO₃ solution (120 ml), chilled for 3 hours, and theresulting precipitate isolated via vacuum filtration. The tackyprecipitate was taken into CH₂Cl₂, washed with KHSO₄ (aq), dried overMgSO₄, recrystallized from EtOAc/hexanes to give a white solid (0.26 g,42%); mass spectrum, m/z 502 (FAB, M+Li).

Example 6 Preparation of[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl, phenylmethyl ester, [3S-[2(1R*,2S*),3α4αβ,8αβ]]- Preparation ofN-Benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane

Part A

To a solution of 75.0 g (0.226 mol ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed in vacuo at 40° C. and theresidue dissolved in ethyl acetate (approx. 1 L). The solution waswashed sequentially with 1M potassium hydrogen sulfate, saturated sodiumbicarbonate and then saturated sodium chloride solutions. After dryingover anhydrous magnesium sulfate and filtering, the solution was removedin vacuo. To the resulting oil was added hexane (approx. 1 L) and themixture warmed to 60° C. with swirling. After cooling to roomtemperature, the solids were collected and washed with 2 L of hexane.The resulting solid was recrystallized from hot ethyl acetate and hexaneto afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S-butanol, mp150-151° C. and M+Li⁺=340. formula:

Part B

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 969 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, whereinCBZ stands for benzyloxycarbonyl. After stirring for fifteen minutes,the solvent was removed in vacuo and the solids dissolved in methylenechloride. After washing with water, drying over magnesium sulfate(MgSO₄), filtering and stripping, one obtains 27.9 g of a white solid.Recrystallization from hot ethyl acetate and hexane afforded 22.3 g (77%yield) of N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp102-103° C. and MH⁺ 298; formula:

Preparation of carbamic acid,[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-,phenylmethylester, [3S-[2(1R*,2S*),3α,4αβ,8αβ]]- also known as carbamic acid,[3S-[3-[[(1,1-dimethylethyl)amino]carbonyl]decahydroisoquinolinyl]-2-hydroxy-2-(phenylmethyl)propyl]-,phenylmethyl ester, [3S-[2(1R*,2S*),3α,4αβ,8αβ]]-

Part A

L-tetrahydroisoquinoline-2-carboxylic acid (24.83 g, 0.140 mol) wassuspended in a solution of 80 mL of 2.5 N sodium hydroxide, 80 mL ofwater, and 80 mL of tetrahydrofuran. To this was added with vigorous.stirring, 32.0 g (0.147 mol) of tert-butylpyrocarbonate in 20 mL oftetrahydrofuran. After 1 hour the pH dropped from 13 to 8.2, at pH=7.8sodium hydroxide (1.5 N) was added dropwise to maintain a pH of 8.8.After the pH stabilized, the contents were extracted with diethylether(2×125 mL). The aqueous phase was acidified (pH˜2.0) with more HCl,after cooling the solution in an ice bath. The precipitate was extractedwith ether, which was then dried over MgSO₄, filtered and concentratedto yield 36.8 grams of crude product which needed no purification (95%yield). The product wasN-tert-butoxycarbonyl-L-tetrahydroisoquinoline-2-carboxylic acid whichhas the following formula:

Part B

N-tert-butoxycarbonyl-L-tetrahydroisoquinoline-2-carboxylic acid (27.7g, 0.10 moles) was dissolved in 50 mL of dimethylformamide, and to thiswas added a warmed solution of 21 g of N-hydroxybenzotriazole in 30 mLof dimethylformamide. The solution was cooled to 10° C. and to this wasadded 19.1 g (0.10 moles) of1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (EDC) andthe solution stirred for 10-15 minutes, at which time 7.3 g (0.100moles) of distilled tert-butylamine was added. After 14 hours thesolution was concentrated and 200 mL of ethyl acetate was added. Theorganic layer was washed with 5% aqueous potassium hydrogen sulfate,saturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered, and concentrated to yield a yellow oil, which was crystallizedfrom warm hexane to yield 15.0 grams of a first crop 45.5% yield. Theproduct was N-tert-butoxycarbonyl-S-tetrahydroisoquinoline-2-carboxylicacid tertbutyl amide which has the following formula:

Part C

N-tert-butoxycarbonyl-S-tetrahydroisoquinoline-2-carboxylic acidtertbutyl amide (10.0 g, 30 mmol) was dissolved in 50 mL of methanol andplaced in a Fischer Porter bottle with 3.2 g of wet rhodium (50 wt %H₂O, 10 wt % rhodium on carbon). The bottle was purged with nitrogen,and charged with 50 psig hydrogen and heated to 50° C. for 24 hours. Thecatalyst was removed by filtration and the methanol evaporated to yielda mixture of (S,S,S) desired isomer and (S,R.R) undesired isomer in a2:1 ratio, respectively. The desired isomer (S,S,S,) was separated bycolumn chromatography on silica gel using a 15-20% ethylacetate hexanegradient elution to yield 6.1 grams of pure isomer (66% yield). Theproduct wasN-tert-butyloxycarbonyl-(S,S,S)decahydroisoquinoline-2-carboxylic acid,tert-butylamide which has the following structure:

Part D

N-tert-butyloxycarbonyl-(S,S,S)decahydroisoquinoline-2-carboxylic acid,tert-butylamide (6.3 g, 18.6 mmol) was dissolved in 30 mL of 4N HCl indioxane and stirred under a nitrogen atmosphere for 1 hour. The solventwas removed and the white solid was suspended in 200 mL ofdichloromethane and washed several times with saturated sodiumbicarbonate. The dichloromethane (CH₂Cl₂) layer was dried over magnesiumsulfate, filtered, and concentrated to yield 3.68 g of freebase (85%yield). The amine product has the following structure:

Part E

The amine from D (3.68 g, 15.4 mmol) and 4.58 g (15.4 mmol) of epoxidefrom Example 1 were dissolved in 50 mL of isopropanol and refluxed undera nitrogen atmosphere for 48 hours. The isopropanol was removed and thecrude solid was chromatographed on silica gel using methanol methylenechloride eluant to provide 8.0 g of pure product (97% yield) identifiedas carbamic acid,[3-[3-[[(1,1-dimethylethyl)amino]-carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)-propyl]-phenylmethylester, [3S-[2(1R*,2S*), 3α,4αβ,8αβ]].

Example 7

Synthesis of

Part A

A solution of carbamic acid,[3-[3-[[(1,1-dimethylethyl)amino]-carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)-propyl]-phenylmethylester,[3S-[2(1R*,2S*),3,4αβ,8αβ]]-(1.01 gm, 1.89 mmole) in N₂ purged THF (20mL) was hydrogenated in the presence of 0.50 gm (50% wt) of 10%Pd/charcoal for 17 hrs at 50 psig of H₂. The catalyst was removed byvacuum filtration through a short plug of packed celite and the solventwas removed in vacuo to give 759 mg (100%) of a white foam. The amineproduct has the following formula:

Part B

To a solution of 100 mg (0.561 mmole) of 2H-thiopyran-3-carboxylate,1,1-dioxide in anhydrous methylene chloride (2.5 mL) was added 143.7 mg(0.561 mmole) of N,Ndisuccinimidyl carbonate and 45.4 μl (0.561 mmole)pyridine. Subsequently, 1 mL acetonitrile was added to form ahomogeneous solution. The resulting solution was stirred under N₂ for 3hrs. The solvent was removed in vacuo and redissolved in ethyl acetate,whereupon it was washed with saturated sodium bicarbonate, 5% KHSO₄, andsaturated sodium chloride. The organic layer was dried with magnesiumsulfate, filtered, and concentrated in vacuo to give 63.2 mg (41%) of asa white solid; mass spectrum m/z 282 (FAB,M+Li) having the followingstructure:

Part C

To a solution of 57 mg (0.207 mmole) of hydroxysuccinimide ester fromPart B in 1.8 mL methylene chloride and 1.2 mL of THF was added 83.15 mg(0.207 mmole) of amine from Part A. the reaction was stirred for 19.5hrs whereupon the solvent was removed in vacuo. The crude product waschromatographed on 10 gm silica gel with 3% methanol in methylenechloride to give 90.2 mg (78% of as a white powder; mass spectrumm/z=568 (FAB,M+Li)

Example 8

Part A

Preparation of phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino-1S-(phenylmethyl)propyl]carbamate

From the reaction ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine(1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8 mmol) andbenzenesulfonyl chloride (483 uL, 3.8 mmol) one obtains phenylmethyl(2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate.Column chromatography onsilica gel eluting with chloroform containing 1%ethanol afforded the pure product. Anal. Calcd. for C₂₉H₃₆N₂O₅S: C,66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

Part B

A solution of 10.1 gm (19.2 mmole) of phenylmethyl ester of the carbamicacid from Part A above in N₂ purged MeOH (100 ml) was hydrogenated inthe presence of 2 gm (20% wt) of 10% Pd/charcoal for 6 hrs. at 50 psigof H₂. The catalyst was removed by vacuum filtration through a shortplug of packed celite and the solvent was removed in vacuo to give 7.41gm (99%) of amine; mass spectrum, m/z=391 (FAB, M+H).

Part C

Preparation of

To a solution of 190 mg (1.07 mmole) of 2H-thiopyran-3-carboxylate,1,1-dioxide in anhydrous DMF (3 mL) was added 240 mg (1.56 mmole)N-hydoxybenzotriazole and 280 mg (1.46 mmole) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC). The resultingsolution was stirred under nitrogen for 10 minutes at room temperatureupon which was added 290 mg (0.91 mmole) of amine from Part B in DMF (5ml) and stirring continued for 18 hrs. Subsequently, the reactionmixture was poured into 50% saturated sodium bicarbonate (aq) andextracted into ethyl acetate. The combined organic layers were driedover magnesium sulfate, filtered and concentrated in vacuo. The crudematerial was recrystallized from ethylacetate/diethylether/hexane togive 300 mg (60%) of a 1:1 mixture of

as a white powder; mass spectrum m/z=557 (FAB, M+Li)

Example 9

Preparation of

Part A

A 25 mL two-necked RB flask, equipped with a reflux condenser anddropping funnel and under a nitrogen atmosphere, was charged witht-butanol (207 uL, 2.2 mmoles) and 5 mL of hexane. Chlorosulfonylisocyanate (192 uL, 2.2 mmoles) in 3 mL of hexane was added dropwise.Upon warming a homogeneous solution was obtained. The solution washeated at gentle reflux for 45 min., then was cooled to r.t. Solvent wasremoved under a steady stream of nitrogen. The crude t-butyl sulfamoylchloride (a liquid) was used without further purification.

Part B

A solution of N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20equivalents) in 650 mL of isopropyl alcohol was heated to reflux for1.25 hours. The solution was cooled to room temperature, concentrated invacuo and then poured into 1 L of stirring hexane whereupon the productcrystallized from solution. The product was isolated by filtration andair dried to give 57.56 g, 92% ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine, mp108.0-109.5° C., MH+m/z=371.

Part C

N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine(370 mg, 1.0 mmole) from Part B was mixed with DIEA (139 uL, 1 mmol) in5 mL of dichloromethane. Chlorotrimethylsilane (126 uL, 1 mmole) wasadded. After 1 h., additional DIEA (160 uL) was added, followed by adichloromethane solution (5 mL) containing 1.1 mmole of t-butylsulfamoyl chloride from Part A. The reaction mixture was stirred for 2days. Solvent was removed under aspirator pressure. The oily residue wastaken p in ethyl acetate and washed with 5% citric acid, saturatedsodium bicarbonate, brine, dried over sodium sulfate and evaporated toan oily residue (380 mg).

The crude product was stirred in 4N HCl in dioxane (6 mL) for 15 min.After the addition of 4 mL of methanol to the reaction mixture, thesolution was stirred for an additional 15 min., then concentrated to anoily residue. The product, phenylmethyl(2R-hydroxy-3-[[(1,1-dimethylethyl)aminosulfonyl](2-an oily residue. Theproduct, phenylmethyl[2R-hydroxy-3-[[(1,1-dimethylethyl)amino]sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]carbamatewas obtained after silica gel chromatography (188 mg, 37%). MS(MH)⁺=506. The carbobenzoxy group was then removed via hydrogenolysis inethanol over 10% palladium on carbon and under 40 psig hydrogen and theresulting amine used directly in the next step.

Part D

To a solution of 42.2 mg (0.24 mmol)( of racemic2H-thiopyran-3-carboxylic acid, 1,1-dioxide in 1.0 mL of anhydrousN,N-dimethylformamide (DMF) and 52 mg (0.34 mmol) ofN-hydroxybenzotriazole, was added 47 mg (0.25 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C.After two hours at 0° C., a solution of 84 mg (0.23 mmol) of free aminefrom Part C in 0.5 mL of DMF was added and the reaction stirred forthree days at room temperature. The DMF was removed in vacuo, ethylacetate added and the solution washed with 5% aqueous citric acid,saturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated to afford 109 mg of crude product. This was chromatographedon silica gel using 2.5% methanol/methylene chloride to afford 64 mg ofpure product as a 1:1 mixture of diasteromers, m/e=532 (M+H).

Example 10 Preparation of t-butyl sulfamoylchoride

Part A

A 25 mL two-necked RB flask, equipped with a reflux condenser anddropping funnel and under a nitrogen atmosphere, was charged witht-butanol (207 uL, 2.2 mmoles) and 5 mL of hexane. Chlorosulfonylisocyanate (192 uL, 2.2 mmoles) in 3 mL of hexane is added dropwise.Upon warming a homogeneous solution is obtained. The solution is heatedat gently reflux for 45 min., then is cooled to r.t. Solvent is removedunder a steady stream of nitrogen. The crude t-butyl sulfamoyl chloride(a liquid) is used without further purification.

Example 11

Preparation of

and

Part A

Preparation of 5-oxo-3-thiomorpholine-1(S)-carboxylic acid

Part A: To a mixture of 4.0 g (22.8 mmol)of D-cysteine hydrochloride in42 mL of methanol and 16 mL of water, was added 9.2 g (45.5 mmol) oftriethylamine, followed by 2.46 g (22.8 mmol) of methyl chloroacetate.After 72 h at room temperature, the solvents were removed under reducedpressure and ethyl acetate added as well as concentrated hydrochloricacid. The layers were separated and the ethyl acetate, dried andconcentrated to afford 203 mg of the desired product, m/e=162(M+H).

Part B: To a solution of 103 mg (0.64 mmol) of the cyclic sulfide frompart A and 147 mg (0.96 mmol) N-hydroxybenzotriazole in 2 mL ofanhydrous N,N-dimethylformamide (DMF) at 0° C., was added 135 mg (0.70mmol) of EDC. After two hours, a solution of 202 mg (0.58 mmol) of aminein 2 mL of DMF from Example. Part was added and the solution stirred atroom temperature for 17 h. The solvents were removed in vacuo, ethylacetate added and washed with saturated aqueous sodium bicarbonate, 5%aquious citric acid, and saturated sodium chloride, dried andconcentrated to afford 230 mg of crude product. Chromatography on silicagel using 3-5% methanol/methylene chloride afforded 196 mg of thedesired product, M/e=499 (M+Li), identified as3-thiomorpholine-1(S)-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-5-oxo-carbonyl](3-methylbutyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-5-oxo-.

Part C: To a solution of 151 mg (0.31 mmol) of the product of part B in10 mL of chloroform was added 200 mg (0.78 mmol) of 67%m-chloroperbenzoic acid. After 16 h at room temperature, methylenechloride was added, the solution washed with 2 M aquious ammoniumhydroxide, dried and concentrated to afford 150 mg of crude product.Chromatography on silica gel using 3-5% isopropanol/methylene chlorideafforded 70 mg of the desired product, m/e=521 or 531 (M+Li), identifiedas 3-thiomorpholine-1(S)-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydroxy-1(S)-phenylmethylpropyl]-3,3,5-trioxo-.

Example 12

Preparation of

and

Part A

Preparation of 5-oxo-3-thiomorpholine-1(R)-carboxylic acid

To a solution of 2.0 g (16.5 mmol) of L-cysteine in 30 mL of methanoland 10 mL of water, was added 3.33 g (33 mmol) of triethylamine and then1.79 g (16.5 mmol) of methyl chloroacetate. After 21 h at roomtemperature, the solvents were removed in vacuo, saturated aqueoussodium bicarbonate was added and the solution extracted with ethylacetate. The aquious layer was then acidified and extracted with ethylacetate. The organic layer was dried and concentrated in vacuo. Theresidue was dried over P₂O₅ in vacuo, ethyl acetate added and theresulting solid collected by filtration to afford 306 mg of the desiredproduct, m/e=161(M+).

Part B: To a solution of 205 mg (1.27 mmol) of the cyclic sulfide frompart A and 292 mg (1.91 mmol) of N-hydroxybenzotriazole in 5 mL ofanhydrous N,N-dimethylformamide at 0° C. was added 268 mg (1.40 mmol) ofEDC. After 2 h, a solution of 398 mg (1.14 mmol) of amine from Example,Part in 2 mL of DMF was added. After 17 h at room temperature, thesolvent was removed in vacuo, ethyl acetate added, washed with saturatedsodium becarbonate, 5% aquious citric acid, saturated soduim chloride,dried and concentrated to afford 448 mg of crude product. Chromatographyon silica gel using 3-5% methanol/methylene chloride afforded 243 mg ofthe desired product, m/e=499 (M+Li), identified as3-thiomorpholine-(1R)-carboxamide,N-[3-([[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-1(R)-hydroxy-1(S)-(phenylmethyl)propyl]-5-oxo-.

Part C: To a solution of 240 mg (0.49 mmol) of the product from Part Bin 10 mL of chloroform was added 314 mg (1.22 mmol) of 67%m-chloroperbenzoic acid. After 17 h at room temperature, methylenechloride was added and washed with 2M aqueous ammonia, water, brine,dried and concentrated to afford 214 mg of crude material.Chromatography on silica gel using 5%-10% isopropanol/methylene chlorideafforded 100 mg of the desired sulfone, m/e=531 or 521(M+Li), identifiedas 3-thiomorpholine-1(R)-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-3,3,5-trioxo-.

Example 13 Preparation of 2H-Thiopyran-3-carboxamide,N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-5,6-dihydro-,1,1-dioxide

Part A

Preparation of 5,6-dihydro-2Hthiopyran-3-carboxylic acid, 1,1-dioxide

To a solution of 205 mg (1.08 mmol) of methyl5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1-dioxide from Example 1 partD in 10 mL of 4N HCl/dioxane, was added 5 mL of water, After stirring atroom temperature for 2 weeks, the solvents were removed in vacuo toprovide a 65:35 mixture, respectively, of the desired acid and unreactedester, respectively. The mixture was used directly in the next step.

Step B

To a solution of 115 mg of the mixture from Part A, and 136 mg (0.89mmol) N-hydroxybenzotriazole in 2 mL of anhydrous N,N-dimethylformamide(DMF) at 0° C., was added 136 mg (o.71 mmol) of EDC. After 2 hours at 0°C., a solution of 206 mg (0.59 mmol) of amine from Example 4, Part A,above, in 1 mL of DMF was added. After 16 hours at room temperature,ethyl acetate was added and washed with aqueous citric acid, water,brine, dried and concentrated to afford 219 mg of crude material. Thiswas chromatographed on silica gel using 0.5-2% methanol/methylenechloride to afford 178 mg (60% yield) of the desired olefinic cyclicsulfone product, m/e=514 (M+Li).

Example 14 Preparation of Tetrahydrothiopyran-4-carboxamide,N-[3-[[[(4-methoxyphenyl)sulfonyl](3-methylbutyl)amino]-2R-hydroxy-15-(phenylmethyl}propyl]]-,1,1-dioxide

Preparation of tetrahydrothiopyran-4-carboxylic acid, 1,1-dioxide

Part A

Preparation of Tetrahydrothiopyran-4-ol

To a solution of 6.36 g (54.7 mmol) of tetrahydropyran-4-one in 200 mLof anhydrous methanol at 0° C. under a nitrogen atmosphere, was added1.04 g (27.4 mmol) of sodium borohydride. After 15 Minutes, 30 mL ofwater was added, the methanol was removed in vacuo and the resultingresidue extracted twice with methylene chloride, dried and concentratedto afford 6.25 g (97% yield) of the desired alcohol, m/e=118 (M+).

Part B

Preparation of Tetrahydrothiopyran-4-ol, O-methanesulfonate

To a solution of 6.25 g (53 mmol) of the alcohol from Part A in 50 mL ofanhydrous methylene chloride and 12.9 mL (159 mmol) of pyridine at 0°C., was added dropwise 7.38 mL (95 mmol) of methanesulfonyl chloride andthe solution allowed to stir at room temperature for sixteen hours.Ethyl acetate (200 mL) was added and the reaction mixture washed with 2Nhydrochloric acid, saturated aqueous sodium bicarbonate, brine, driedand concentrated to afford 10.4 g of crude material. Chromatography onsilica gel using 0.5% methanol/methylene chloride afforded 9.88 g (95%yield) of the desired mesylate, m/e=197 (M+H).

Part C

Preparation of Tetrahydrothiopyran-4-cyano

To a solution of 7.75 g (39.4 mmol) of the mesylate from Part B in 100mL of anhydrous N-methylpyrrolidinone was added 19.3 g (395 mmol) ofsodium cyanide. The mixture was heated at 90° C. for twenty hours,cooled, 200 mL of water added and the solution extracted three timeswith diethyl ether. The organic layer was dried and concentrated toafford 15.8 g of material which still contained N-methylpyrrolidinone.Chromatography on silica gel using 0.5% methanol/methylene chlorideafforded a mixture of the desired nitrile, contaminated with the olefinresulting from elimination of the mesylate. Chromatography on silica gelusing 10% ethyl acetate/hexane afforded 1.94 g (39% yield) of thedesired nitrile, m/e=128 (M+H).

Part D

Preparation of Tetrahydrothiopyran-4-carboxamide

To 3 mL of concentrated sulfuric acid, was added 813 mg (6.4 mmol) ofthe nitrile from Part C and the mixture heated at 45° C. for sixteenhours. The solution was cooled and poured into 50 mL of ice and water,the solids collected, dissolved in ethyl acetate, dried and concentratedto afford 614 mg (66% yield) of the desired amide, m/e=145 (M+).

Part E

Preparation of tetrahydrothiopyran-4-carboxylic Acid

To a solution of 601 mg (4.1 mmol) of the amide from Part D in 10 mL ofmethanol was added 828 mg (21 mmol) of sodium hydroxide and the mixtureheated at reflux for sixteen hours, 5 mL of water added and heatingcontinued for 72 hours. The methanol was removed in vacuo, 2Nhydrochloric acid added and the solution extracted with ethyl acetate,dried and concentrated to afford 571 mg (94% yield) of the desired acid,m/e=147 (CI,M+H).

Part F

Preparation of Tetrahydrothiopyran-4-carboxylic Acid, 1,1-dioxide

To a solution of 200 mg (1.3 mmol) of the acid from Part E in 9 mL ofacetic acid was added 620 mg (5.5 mmol) of 30% aqueous hydrogenperoxide. After heating at reflux for 1.5 hours, the colution wascooled, sodium sulfite added to quench any excess oxidizing agent (usingpotassium iodide/starch paper for detection), the volatiles removed invacuo and the residue extracted with warm ethyl acetate, which wasquickly filtered and concentrated to afford 140 mg (59% yield) of thedesired sulfone, m/e=179 (M+H).

Tetrahydrothiopyran-4-carboxamide,N-[3-[[[(4-methoxyphenyl)sulfonyl](3-methylbutyl)amino]-2R-hydroxy-1S-(phenylmethyl)propyl]]-,1,1-dioxide

To a solution of 53 mg (1.1 mmol) of tetrahydrothiopyran-4-carboxylicacid, 1,1-dioxide and 62 mg (1.5 mmol) of N-hydroxybenzotriazole in 2 mLof anhydrous N,N-dimethylformamide (DMF) at 0° C., was added 62 mg (1.2mmol) of EDC. After 2 hours at 0° C., a solution of3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-2R-hydroxy-3S-(phenylmethyl)propylaminein 1 mL of DMF was added. After sixteen hours at room temperature, thevolatiles were removed in vacuo, ethyl acetate acid, washed with 5%aqueous citric acid, saturated sodium bicarbonate, brine, dried andconcentrated to afford 142 mg of crude product. This was chromatographedon silica gel using 2.5% methanol/methylene chloride to afford 127 mg(83% yield) of the desired product.

Example 15 Assays

Part A: Enzyme Assay

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in Examples 4, 4a, 7, 8 and 9 inhibited the HIV enzyme in anamount described as an IC₅₀ ranging from about 3 nanomolar to about 140nanomolar as shown in Table 1. The calculated IC₅₀ indicates theconcentration providing inhibition of 50%, i.e., the concentration atwhich the inhibitor compound reduces enzyme activity by 50%). The enzymemethod is described below. The substrate is2-aminobenzoyl-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control isMVT-101 [Miller, M. et al, Science, 246, 1149 (1989)]. The assayconditions are as follows: Assay buffer: 20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 IM.

HIV protease is diluted in the assay buffer to a final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10×the test concentration; 10 IL of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 IL of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

TABLE 1

Examples Q IC₅₀ EC₅₀ TD₅₀ 4

 13 nM  63 NM 308,000 nM 8

 4 nM  19 NM  46,000 nM 7

 3 nM  12 nM  48,000 nM 4a

 46 nM 295 nM 420,000 nM 9

140 nM — —

Thus, the compounds of the present invention are effective antiviralcompounds and, in particular, are effective retroviral inhibitors asshown above. Thus, the subject compounds are effective HIV proteaseinhibitors. It is contemplated that the subject compounds will alsoinhibit other viruses such as human T-cell leukemia virus, respiratorysyncitial virus, hepadnavirus, cytomegalovirus and picornavirus by theproposed inhibition of post translational proteolytic processing events.Thus, the subject compounds are effective in the treatment and/orprophylaxis of retroviral infections.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, butyl chloride, bromides, and iodides; dialkyl sulfateslike dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halidessuch as decyl, lauryl, myristyl, and stearyl chlorides, bromides andiodides, aralkyl halides like benzyl and phenethyl bromides, and other.Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular made of administration.

The dosage regimen to give relief from or ameliorate a disease condition(i.e., treatment) or protecting against the further spreading of theinfection (i.e., prophylaxis) with the compounds and/or compositions ofthis invention is selected in accordance with a variety of factors,including the type, age, weight, sex, diet and medical condition of thepatient, the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized and whether thecompound is administered as part of a drug combination. Thus, the dosageregimen actually-employed may vary widely and therefore deviate from thepreferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The parental asused herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pill, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Pharmaceutically acceptable carriers encompass all the foregoing and thelike.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT or with N-butyl-1-deoxynojirimycin for theprophylaxis and/or treatment of AIDS. When administered as acombination, the therapeutic agents can be formulated as separatecompositions which are given at the same time or different times, or thetherapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andcondition.

What is claimed is:
 1. A compound of the formula (I″)

or a pharmaceutically acceptable salt, prodrug or ester thereof whereinW represents

wherein Y′ represents 0,S and NR¹⁵ wherein R¹⁵ represents hydrogen andradicals as defined for R³; and t represents 0,1 and 2; t′ represents 1and 2; u represents 0, 1 and 2; R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁸, R⁴⁹, R⁵⁰ andR⁵¹ independently represent hydrogen and alkyl; R⁴⁴, R⁴⁵, R⁴⁶, and R⁴⁷independently represent hydrogen, alkyl and hydroxy; or one of (a) R⁴⁰together with R⁴⁸, (b) R⁴³ together with R⁴⁵, (c) R⁴⁵ together with R⁴⁷and (d) R⁴⁷ together with R⁴⁸ represent a bond; or one of (a) R⁴⁴together with R⁴⁵ and the carbon to which they are attached, (b) R⁴⁶together with R⁴⁷ and the carbon to which they are attached (c) R⁵⁰together with R⁵¹ and the carbon to which they are attached represent acarbonyl; R⁶ represents hydrogen and alkyl radicals; R² representsalkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, whichradicals are optionally substituted with a substituent selected from thegroup consisting of alkyl radicals, —NO₂,CN, CF₃, —OR⁹, —SR⁹, andhalogen radicals, wherein R⁹ represents hydrogen and alkyl radicals; Qis

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl or aheteroaryl radical, thioalkyll, alkylthioalkyl, and arylthioalkylradicals and the sulfone or sulfoxide derivatives thereof; Yindependently represents moieties as defined for Y′; X represents N, CHor O; R⁴ and R⁵ independently represent hydrogen and radicals as definedby R³, or when X represents N, R⁴ and R⁵ together with the nitrogen atomto which they are bonded represent heterocycloalkyl and heteroarylradicals, or and when X represents CH, R⁴ and R⁵ together with thecarbon atom to which they are bonded represent a cycloalkyl radical,with the proviso R⁵ is nothing when X is O; R^(4′) and R^(5′) togetherwith the nitrogen atom to which they are bonded represent anN-heterocyclic moiety; R^(4″), R⁹ and R^(9′) independently representsradicals as defined by R³; q represents 1 or 2; n represents from 0 to6; R⁷ and R^(7′) independently represent radicals as defined for R³ andamino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine,glutamine, and t-butylglycine or R⁷ and R^(7′) together with the carbonatom to which they are attached form a cycloalkyl radical; R⁸ representscyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF³ and NR¹⁶R¹⁷;wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent hetrocycloalkyl andheteroaryl radicals; and wherein R³, X, R⁴, R⁵, R^(4′), R^(5′), R^(4″),R⁹, R^(9′), R⁷, R^(7′), or R⁸ are selected such that Q includes animidazolyl.
 2. A compound of claim 1 wherein W represents (a) whereinR⁶, R², Q, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ are as definedin claim
 1. 3. A compound of claim 2 wherein R⁴ and R⁵ together with thenitrogen to which they are attached represent a 5 to 8 memberedheterocycloalkyl ring.
 4. A compound of claim 2 represented by theformula (II):

or a pharmaceutically acceptable salt, prodrug or ester thereof, andwherein: t; R²; R⁶; Y′; R^(4′) and R^(5′) are as defined in claim
 1. 5.A compound of claim 4 wherein Y′ represents O, t represents 1 and R⁶represents hydrogen.
 6. A compound of claim 4 wherein R² representsbenzyl, p-fluorobenzyl, cyclohexylmethyl, 2-naphthylmethyl, n-butyl andisobutyl.
 7. A compound of claim 2 of the formula (III)

or a pharmaceutically acceptable salt, prodrug or ester thereof, andwherein t; R²; Y′; R ⁶; R²; R³; R^(4″) and q are as defined in claim 2.8. A compound of claim 7 wherein R^(4″) represents an aryl or heteroarylradical.
 9. A compound of claim 2 of formula IV:

wherein R² represents alkyl, aryl cycloalkyl, cycloalkylalkyl, andaralkyl radicals, which radicals are optionally substituted with asubstituent selected from the group consisting of alkyl radicals, —NO₂,CN, CF₃, —OR⁹, —SR⁹, and halogen radicals, wherein R⁹ representshydrogen or alkyl radicals; R³ represents hydrogen, alkyl, haloalkyl,alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- and disubstitutedaminoalkyl radicals, wherein said substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl or aheteroaryl radical thioalkyll, alkylthioalkyl, or arylthioalkyl radicalsor the sulfone or sulfoxide derivatives thereof; R⁴ and R⁵ independentlyrepresent hydrogen and radicals as defined by R³, or R⁴ and R⁵ togetherwith the nitrogen atom to which they are bonded representheterocycloalkyl and heteroaryl radicals; R⁶ represents hydrogen oralkyl radicals; t represents 0,1 or 2; and Y′ represents O,S or NR¹⁵wherein R¹⁵ represents hydrogen or radicals as defined for R³.
 10. Aprocess for reacting cyclic sulfone of the formula: WOH with one of agroup compounds consisting of

and replacing P with R⁶ to obtain a compound of the Formula I″ of claim1.